Discussion about the Treatment of Alzheimer’s Disease with Yisui Fuyong Decoction Based on Synaptic Plasticity

Guohua TANG, Wenqiang TAO

Chongqing Traditional Chinese Medicine Hospital, Chongqing 502682, China

Abstract For Alzheimer’s disease (AD), the earliest symptom is memory loss, which runs throughout the disease. The mutual growth and decline of long-term potentiation (LTP) and long-term depression (LTD) in synaptic plasticity is the basic condition of learning and memory. In the early stage of AD, there is no significant change in synaptic plasticity, so the treatment should mainly focus on warming yang and replenishing qi. In the middle stage of AD, LTP is continuously damaged and reduced, and synaptic plasticity is destroyed, such as weakness of the spleen and stomach, causing stagnation of endogenous retention of phlegm in the brain, so the treatment should focus on enriching yin and tonifying yang, resolving phlegm to remove stagnation. In the late stage of AD, due to excessive deposition of amyloid and other metabolites, neurotoxins are produced and brain atrophy is aggravated, such as depression leading to stasis, phlegm and stasis binding together, long term of stasis turning to heat toxin, which invades the brain, excessive heat damages yin, then both yin and yang are damaged, finally, the brain collateral loses nutrition, so the treatment should focus on replenishing essence and reinforcing marrow, detoxifying and resolving stasis. Yisui Fuyong Decoction can replenish essence and reinforce marrow to nourish yin, warm yang and tonify qi to strengthen yang, combine phlegm resolving, stasis elimination and collateral vessels dredging, realizing the treatment effects in all three stages of synaptic plasticity.

Key words Alzheimer’s disease (AD), Yisui Fuyong Decoction, Synaptic plasticity, Yin in physique and yang in function, Brain

1 Introduction

Alzheimer’s disease (AD) is a disease with the highest morbidity rate, clinically characterized by slow-onset mental decline and personality abnormalities, with senile plaques, neurofibrillary tangles, and neuronal loss as the main pathological changes[1-2]. From the perspective of yin in physique and yang in function to treatment encephalopathy (brain disease), we proposed the method of replenishing essence and reinforcing marrow to nourish yin, warming yang and tonifying qi to strengthen yang. We created Yisui Fuyong Decoction treatment, established the prescription system of yin in physique and yang in function to treat encephalopathy, and applied it in clinical practice, the clinical effect was good[3]. Modern research shows that the central link of AD may be the change of synaptic plasticity. Based on yin in physique and yang in function to treat encephalopathy, we explored the mechanism of encephalopathy treatment.

2 Core pathogenic mechanism of AD

2.1 Concept of synaptic plasticitySynapse is composed of presynaptic membrane, synaptic cleft, and postsynaptic membrane. It is the main way of information transmission between neurons or between neurons and effectors, and it is a key part of synaptic plasticity. Synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity[4-5]. Its material basis involves proteins, receptors, neurotransmitters, and messenger molecules in neurons and synapses. The normal functioning of brain neurons depends on excitatory synaptic plasticity, which includes various forms, the most classic being long-term potentiation (LTP) and long-term depression (LTD). The mutual growth and decline of long-term potentiation (LTP) and long-term depression (LTD) in synaptic plasticity is the basic condition of learning and memory[6].

2.2 Relationship between synaptic plasticity and learning and memoryLearning and memory are one of the advanced functions of the brain. Studies have shown that the hippocampus is the main functional area of learning and memory. Through training rats by the shuttle box avoidance model, and making a record of the stimulation and electrode data of the anterior perforating fibers and granule cells in the dentate gyrus before and after training, Matthies Hetal.[7]observed the changes of LTP before and after training, and found that the amplitude of the group spikes evoked before stimulation was significantly larger than that before training, and memory and performance were positively correlated. Using the same method to study old and young rats, Barnesetal.[8]found that old rats have poorer memory and weaker LTP effect than young rats, indicating that animal learning and memory ability is related to LTP effect. Martinetal.[9]put forward the hypothesis of "synaptic plasticity and memory", pointing out that in the process of learning and memory, the LTP efficiency generated by related synapses can enhance memory, and synaptic plasticity changes are the basic conditions for memory storage. According to the study of Li Weietal.[10], LTP effect is related to memory formation, while LTD is related to memory forgetting. More studies have shown that improved memory is related to enhanced LTP effect and weakened LTD inhibition; reduced memory is related to impaired LTP effect and LTD facilitation[11-13].

2.3 Synaptic plasticity and ADThe earliest symptom of AD is memory loss, and it runs through the disease. Neurofibrillary tangles and amyloid deposition are typical pathological features of the disease[14]. In the early stage of AD, LTP is damaged but the body can still compensate, and the symptoms are not obvious. As the disease progresses, LTP damage is aggravated, and amyloid cannot be excreted normally, tangles with neurofibrillary tangles, resulting in excitotoxicity, which affects neurons, destroys synapses, aggravates synaptic plasticity and LTP damage, and causes a decline in learning and memory. Studies have shown that the weakening of LTP efficacy and synaptic plasticity impairment are positively correlated with the decline of AD learning and memory[15].

3 Brain belonging to yin in physique and yang in function

In 2015, we put forward the theory of yin in physique and yang in function. According to records ofLingshu·Jingmai(Miraculous Pivot · Meridian Vessel), the first generation of human is formed in the essence, and the brain is formed from the development of the essence. Kidney essence is composed of congenital essence and acquired essence. The congenital essence comes from the endowment of the parents, and the acquired essence is transformed by the water and grain essence. The refined substances and body fluids belong to yin fluid, so the physique is yin. The brain is the master of the spirit, the master of sensory movement, and spiritual consciousness. It governs spirit, ethereal soul, corporeal soul, ideation, and will. “For all 12 meridian vessels and 365 collateral vessels, the blood and qi move upward to eyes and open to orifices”, reflecting the characteristic of yang in function, so the brain belongs to yin in physique and yang in function.

4 Application of Yisui Fuyong Decoction in the treatment of AD

4.1 Yisui Fuyong DecoctionThe prescription that best reflects yin in physique and yang in function is Dihuang Yinzi Decoction inCompleteRecordofSacredBenevolence. This has the functions of nourishing kidney yin, invigorating kidney yang, opening orifices and resolving phlegm. It is mainly used for kidney deficiency and weakness, and turbid phlegm upward. This prescription is characterized as treating both upper and lower, treating both manifestation and root cause of disease, but focusing on treatment the lower and the root cause; moderately replenishing the middle, opening with closing; nourishing but not slimy, warm but not dry; neutrally supplementing kidney yin and yang, and resolving phlegm and moving qi, reflecting the characteristic of yin in physique and yang in function. The root cause of brain disease is deficiency and weakness of liver and kidney, combined with excessive pathogen such as qi stagnation, phlegm obstruction, and blood stasis. Therefore, based on Dihuang Yinzi Decoction, we created Yisui Fuyong Decoction, which is composed of 30 g of Rehmanniae Radix Praeparata, 30 g of Corni Fructus, 30-60 g of Astragali Radix, 30 g of Codonopsis Radix, 10 g of Psoraleae Fructus, 30 g of Alpiniae Oxyphyllae Fructus, 15 g of Cuscutae Semen, 10 g of Morindae Officinalis Radix, 20 g of Ostreae Concha, 10 g of Salviae Miltiorrhizae Radix Et Rhizoma, 5 g of Scorpio, 10 g of Bombyx Batryticatus, 1-2 pieces of Scolopendra, 10 g of Schisandrae Chinensis Fructus, 10 g of Polygalae Radix, 10 g of Cervi Cornu Degelatinatum, 30 g of Vinegar Processed Testudinis Carapax Et Plastrum, and 10 g of Amomi Fructus. In the prescription, Rehmanniae Radix Praeparata and Corni Fructus have functions of nourishing kidney yin, Psoraleae Fructus and Morindae Officinalis Radix can warm and invigorate kidney yang, so they are taken as sovereign drugs; minister drugs are Astragali Radix and Codonopsis Radix that can replenish qi, generate essence and reinforce marrow, nourish spleen and kidney, essence and blood come from the same origin; Alpiniae Oxyphyllae Fructus and Cuscutae Semen can neutrally supplement kidney and liver, benefit essence and reinforce marrow; assistant drugs include Ostreae Concha, Salviae Miltiorrhizae Radix Et Rhizom, Bombyx Batryticatus, Scorpio, Scolopendra, and Amomi Fructus. Ostreae Concha can remove stasis, Salviae Miltiorrhizae Radix Et Rhizoma can invigorate the blood and eliminate stasis, Bombyx Batryticatus, Scorpio, and Scolopendra have functions of dispelling pathogenic wind and eliminating phlegm, and Amomi Fructus has functions of dissipating and warming through pungent nature, resolving dampness and moving qi to prevent excessive dampness. Courier drugs are two pairs of drugs: Polygalae Radix and Schisandrae Chinensis Fructus; Cervi Cornu Degelatinatum and Vinegar Processed Testudinis Carapax Et Plastrum. Polygalae Radix opens the heart and brain in the upper, while Schisandrae Chinensis Fructus leads downward to kidney. Water and fire coordinate each other to promote blood and qi move normally and balance yin and yang. Turtle (Chinemysreevesii) and deer (Cervuselaphus) are clever and long-lived. The turtle head is often hidden in the belly, it can lead to conception vessel, so we take its shell to tonify heart, kidney, and blood, and draw the support of conception vessel to reinforce yin. The deer head often turns to the tail, it can lead to governor vessel, so we take its antler to tonify the life, essence and qi, and draw the support of governor vessel to reinforce yang. In addition, Testudinis Carapax Et Plastrum can enrich yin and subdue yang, replenish kidney and fortify stomach; Cervi Cornus Colla can tonify kidney yang and generate essence and blood. Combined use of Testudinis Carapax Et Plastrum and Cervi Cornu Degelatinatum can supplement yin and yang, regulate conception vessel and governor vessel, so as to greatly tonify kidney yin and yang, treat deficiency and reinforce weakness. InAncientandModernFamousPrescriptions, Li Zhongzi stated that human beings have three treasures, namely, essence, qi, and spirit, which are foundation of life. If the essence is damaged, qi will not generate; if qi is damaged, the spirit will not generate; if the essence is deficient, it should be replenished. The deer obtains complete yang qi on earth, so Cervi Cornu is used to unblock the governor vessel and achieve sufficient essence and long life. Turtle obtains complete yin qi on earth, so Testudinis Carapax Et Plastrum is used to unblock conception vessel, to realize sufficient qi and long life. Both drugs belong to qi and blood, have the purest flavor, and obtain the original essence of nature. This is the method of using bamboo to make up the bamboo damage. Accordingly, the essence is generated and qi is effulgent, effulgent qi brings high spirit, finally achieving long life.

Patients with obvious yang deficiency can be given with 10 g of Aconiti Lateralis Radix Praeparata and 10 g of Zingiberis Rhizoma to boost yang and resolve phlegm, and warm the lower origin. Patients with not obvious yang deficiency can be given with 10 g of Typhonii Rhizoma and 10 g of Angelicae Pubescentis Radix to clear brain and remove phlegm. Firstly, the whole prescription has functions of regulating the five internal organs (heart, liver, spleen, lungs and kidneys), and reinforce qi and blood. Secondly, Schisandrae Chinensis Fructus and Polygalae Radix can boost kidney essence, and Cervi Cornu Degelatinatum and Vinegar Processed Testudinis Carapax Et Plastrum can replenish marrow and spirit. Thirdly, the prescription can dispel pathogenic wind and eliminate phlegm, eliminate the pathogenic factors and reinforce the healthy qi. All drugs jointly take the effect of replenishing essence, reinforcing the marrow, to tonify yin in application, warming yang, nourishing qi to tonify yang in functions, accordingly realizing the combined function of resolving phlegm and unblocking meridian vessels.

4.2 Yisui Fuyong Decoction and three stages of AD synaptic plasticityIn the opinion of Zhang Xi,etal.[16], in the early stage of AD, the treatment should mainly focus on warming yang and replenishing qi; in the middle stage of AD, LTP is continuously damaged and reduced, and synaptic plasticity is destroyed, amyloid metabolism disorder, then soluble amyloid can be detected in patients, such as weakness of the spleen and stomach, causing stagnation of endogenous retention of phlegm in the brain, so the treatment should focus on enriching yin and tonifying yang, resolving phlegm to remove stagnation; in the late stage of AD, due to excessive deposition of amyloid and other metabolites, neurotoxins are produced, neurons are damaged due to synaptic excitotoxicity invasion, and a large number of them are lost, and the number of synapses is greatly reduced, brain atrophy is aggravated, and a large number of senile plaques and fibrotic tangles can be detected, such as depression leading to stasis, phlegm and stasis binding together, long term of stasis turning to heat toxin, which invades the brain, excessive heat damages yin, then both yin and yang are damaged, finally, the brain collateral loses nutrition, so the treatment should focus on replenishing essence and reinforcing marrow, detoxifying and resolving stasis. Yisui Fuyong Decoction can replenish essence and reinforce marrow to nourish yin, warm yang and tonify qi to strengthen yang, combine phlegm resolving, stasis elimination and collateral vessels dredging, realizing the treatment effects in all three stages of synaptic plasticity. Based on synaptic plasticity to explore the effect of Yisui Fuyong Decoction in the treatment of AD, we integrated the key pathogenesis of the disease with the TCM theory, in order to provide a reference for the treatment of AD.